P41 NO EVIDENCE OF B-CELL MATURATION ANTIGEN (BCMA) EXPRESSION LOSS OR SYSTEMIC IMMUNE IMPAIRMENT AFTER TREATMENT WITH THE BCMA-TARGETED ANTIBODY-DRUG CONJUGATE BELANTAMAB MAFODOTIN IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
Authors: D.E. Lowther, E.A. Houseman, G. Han, E. Kleanthous, D. Knoblock, X. Zhou, S. Banerjee, S. Patel, D. Figueroa
Journal: HemaSphere (2023)

Objectives: Belantamab mafodotin (belamaf)—an antibody-drug conjugate targeting B-cell maturation antigen (BCMA)—demonstrated deep and durable responses in the DREAMM-2 trial of patients with relapsed/refractory multiple myeloma (RRMM). Belamaf eliminates multiple myeloma (MM) cells by both direct cell killing and anti-MM immune response. We explored whether complete target loss and/or immune impairment were observed in belamaf-treated patients in the DREAMM-1 and -2 trials. Methods: DREAMM-1 was a Phase 1 dose-escalation study to investigate the safety, pharmacokinetics/pharmacodynamics, immunogenicity and clinical activity of belamaf. DREAMM-2 was an open-label, two-arm, Phase 2 study of belamaf (2.5 or 3.4 mg/kg, once every three weeks). Both trials enrolled adults with RRMM with ≥3 prior lines of therapy including an immunomodulatory drug, proteasome inhibitor and an anti-CD38 monoclonal antibody (DREAMM-2 only). Free serum (s)BCMA—a shed form of BCMA that circulates in the blood after membrane cleavage—was measured using an electrochemiluminescence assay. Absolute sBCMA concentrations were examined at baseline, with absolute concentration and fold-change from baseline assessed at best achieved response and latest progression. After the first post-infusion timepoint, samples were taken >4 days post infusion. In this post hoc analysis, association of sBCMA with time-on-study was modelled using a linear mixed model. Immune cell populations in peripheral blood were analysed using flow cytometry and clinical hematology tests. Neutrophil-to-lymphocyte ratio and total lymphocyte counts were modelled by categorical patient visit adjusted for continuous or count-based biomarkers; T-cell subpopulation counts were modelled using negative binomial mixed effects models. Results: At progression, sBCMA levels were detectable in 98% (50/51) of eligible patients in DREAMM-1 and in 98.9% (181/183) of eligible patients in DREAMM-2, regardless of response status. Decreased sBCMA versus predose levels was observed immediately post infusion in all response groups. In non-responders, sBCMA returned to predose levels within one cycle. Responders (≥partial response) had a quantitatively lower but measurable sBCMA level. In 97% (64/66) of patients who responded but later progressed in DREAMM-2, sBCMA levels dropped markedly during response but returned to near baseline upon progression. Previously, sBCMA levels have been shown to correlate with disease burden markers (e.g., M-protein) and International Staging System stage; we modelled sBCMA correcting for these associations to evaluate on-treatment dynamics, predicting a decrease in sBCMA with increasing time-on-treatment. After correcting for lower average baseline and on-treatment sBCMA levels in responders, sBCMA levels tended to decrease over time. There were no changes in immune cell ratios or major cell populations, regardless of response status. Immune cell profiles of responders and non-responders were similar and consistent over time. Conclusions: We found no evidence that BCMA expression is completely lost after belamaf treatment, suggesting that complete target loss is not the primary mechanism driving tumour escape in these patients. Regardless of response status, belamaf does not appear to negatively impact total lymphocyte numbers while mediating anti-MM activity. These data may help inform sequencing of belamaf with other BCMA-targeted therapies.